The primary goal of this project has been the elucidation of the reactive metabolites which are responsible for the carcinogenic, cytotoxic, and mutagenic activity of benzo(a)pyrene and other polycyclic hydrocarbons. The approach taken consists of: 1) synthesis of primary oxidative metabolites as well as selected secondary oxidative metabolites. 2) study of the metabolism of these hydrocarbons with liver microsomes, as well as purified and reconstituted cytochrome P-450 systems with and without epoxide hydrase, 3) tests for inherent mutagenicity of the synthetic metabolites toward bacterial and mammalian cells, 4) elucidation of the roles of the cytochrome P-450 system and epoxide hydrase in potentiating or obliterating the mutagenicity of these metabolites, 5) determination of the carcinogenic activity in vivo for these compounds, 6) determination of the rate and nature of the products formed when reactive metabolites such as arene oxides and diol epoxides react with biopolymers and less complex chemical analogs. Attempts to formulate a general theory of hydrocarbon-induced carcinogenesis are in progress. BIBLIOGRAPHIC REFERENCES: Seifried, H.E., Birkett, D.J., Levin, W., Lu, A.Y.H., Conney, A. H. and Jerina, D.M.: Metabolism of Benzo(a)pyrene V. Effect of 3-Methylcholanthrene Pretreatment on Metabolism By Microsomes from Lungs of Genetically "Responsive" and "Non-Responsive" Mice. Arch Biochem. Biophys. 178: 256-263, 1977. Bresnick, E., McDonald, T.F., Yagi, H., Jerina, D.M., Levin, W., Wood, A.W. and Conney, A.H.: Epidermal Hyperplasia After Topical Application of Benzo(a)pyrene, Benzo(a)pyrene Diol Epoxides, and Other Metabolites. Cancer Res. 37: 984-990, 1977.